The risk of venous thromboembolism (VTE) is substantially increased in patients with cancer especially those who are hospitalized, in active treatment, and with major medical comorbidities.1 VTE in patients with cancer is associated with serious adverse consequences, including VTE recurrence, major bleeding and early mortality.2 Since its derivation, the Khorana risk score for cancer-associated thrombosis has been validated in multiple prospective and retrospective studies.3-5 Several randomized controlled trials (RCTs) of primary prevention in the ambulatory cancer setting for those at increased risk for VTE have confirmed that low-molecular-weight heparins (LMWHs) can significantly reduce the risk of VTE with only a modest increase in major bleeding risk.6
Recent RCTs and meta-analyses have directly compared direct oral anticoagulants (DOACs) with LMWH for the treatment of established VTE in patients with cancer.7-9 While the absolute risk differences were small, the RCTs and overview demonstrated that the risk of recurrent VTE was lower while the risk of bleeding greater with DOACs compared with LMWH. Subsequently, the Khorana risk score has been used to select high-risk ambulatory cancer patients for accrual to two thromboprophylaxis trials comparing low-dose DOACs with placebo in patients receiving chemotherapy for cancer at intermediate- or high-risk for VTE (AVERT and CASSINI).10,11
Pooled results from these DOAC placebo-controlled thromboprophylaxis trials in higher risk ambulatory patients receiving cancer therapy demonstrated a significant reduction in overall VTE incidence in those receiving a DOAC prophylactically.12 A small, nonsignificant increased risk of major bleeding and clinically relevant non-major bleeding (CRNMB) with DOACs was observed.
Clinical Practice Guidelines for the Treatment and Prevention of VTE
Several clinical practice guidelines addressing VTE treatment and prevention in patients with malignant disease have been updated, including that from the American Society of Clinical Oncology (ASCO), which was established nearly 15 years ago.13,14 The latest of these are new guidelines for the prevention and treatment of VTE in patients with cancer from the American Society of Hematology, which has now issued a total of 10 guidelines on the management of VTE in a range of clinical situations.
ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The GRADE approach was used to assess evidence and make recommendations, which were subject to public comment. These guidelines provide 34 recommendations covering appropriate thromboprophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure and in ambulatory patients with cancer receiving systemic therapy.
The recommendations also address the use of anticoagulation for the initial (first week), short- (subsequent 3–6 months) and long-term (>6 months) treatment of VTE in patients with cancer, including those with central venous catheter and patients with recurrent VTE despite anticoagulation treatment. Abbreviated summaries of the final recommendations from the ASH VTE Cancer Guidelines are summarized in Table 1.
Table 1. ASH Recommendations for the Prevention and Treatment of Venous Thromboembolism in Patients with Cancer – Data taken from Lyman et al15
|Primary prophylaxis in hospitalized medical patients with cancer without VTE
|Thromboprophylaxis in patients with cancer undergoing surgery
|Thromboprophylaxis in ambulatory patients with cancer receiving systemic therapy
|Thromboprophylaxis in patients with cancer with central venous catheter
|Initial treatment (first week) in patients with active cancer and VTE
|Short-term treatment (3–6 months) in patients with active cancer
|Long-term treatment (>6 months) in patients with active cancer and VTE
Evidence-based guidelines from ASH and other professional organizations can provide clinicians with a balanced resource for the use of anticoagulants in the specific management of patients with cancer. The high level of concordance in updated recommendations across currently available clinical practice guidelines is reassuring. However, further efforts are needed to improve the dissemination, implementation and utilization of available guidelines in order to bring clinical practice into compliance with current recommendations. While the use of recently validated clinical risk models for VTE among ambulatory cancer patients is promising, new biomarkers for VTE and bleeding complications are needed to further improve selection of high-risk patients for more individualized or personalized prophylactic strategies. It will only be through optimal application of current strategies along with increased investment into basic and translational clinical research that further reductions in the morbidity and mortality associated with thromboembolic complications in patients with cancer can be realized.
The recent ASH clinical practice guideline recommendations include the use of thromboprophylaxis with LMWHs in hospitalized patients with cancer. The use of LMWH, apixaban or rivaroxaban is recommended in ambulatory patients receiving systemic cancer therapy at high risk for thrombosis. Either no thromboprophlaxis or prophylaxis with apixaban or rivaroxaban is instead recommended in patients receiving systemic cancer therapy at intermediate risk for thrombosis.
In patients undergoing major cancer surgery, thromboprophylaxis with LMWH or fondaparinux with or without mechanical prophylaxis is recommended in those with low bleeding risk while mechanical prophylaxis alone is encouraged in those with at high bleeding risk. Initial treatment with LMWH, apixaban or rivaroxaban is recommended for the initial (first week) of treatment of thrombosis of patients with active cancer. Short-term treatment (3–6 months) and long-term secondary prophylaxis (>6 months) with LMWH or a DOAC are recommended for patients with active cancer and established VTE. Finally, clinical decision-making related to thromboprophylaxis or treatment of VTE in patients with cancer should be based on an assessment of the individual patient’s risk for both thrombosis and major bleeding following full discussion of the potential benefits and harms.
It is essential to understand that patients may have different values and preferences than those held by their clinician with respect to the goals of anticoagulation and the assessment of risks and benefits, which may change over time and must be continuously reassessed.
- Khorana AA, Francis CW, Culakova E, et al. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005;104:2822-9.
- Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011;117:1334-49.
- Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902-7.
- Ay C, Simanek R, Vormittag R, et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood 2008;112:2703-8.
- van Es N, Ventresca M, Di Nisio M, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: An individual patient data meta-analysis. J Thromb Haemost 2020;18:1940-1951.
- Schunemann HJ, Ventresca M, Crowther M, et al: Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis. Lancet Haematol 2020;7:e746-e755.
- Young AM, Marshall A, Thirlwall J, et al: Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol 2018;36:2017-2023.
- Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378:615-624.
- Li A, Garcia DA, Lyman GH, et al: Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res 2019;173:158-163.
- Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019;380:711-719.
- Khorana AA, Soff GA, Kakkar AK, et al: Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019;380:720-728.
- Li A, Kuderer NM, Garcia DA, et al. Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: a systematic review and meta-analysis. J Thromb Haemost 2019;17(12):2141-2151.
- Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020;38:496-520.
- Lyman GH, Kuderer NM. Clinical practice guidelines for the treatment and prevention of cancer-associated thrombosis. Thromb Res 2020;191(Suppl 1):S79-S84.
- Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021;5:927-974.